NEW ENGLAND DRUG METABOLISM DISCUSSION GROUP

NEWS + EVENTS

NEDMDG 2024 Spring Meeting
Wed. March 13th, 2024 at 5:30 – 8:30 pm EST

Agios Pharmaceuticals
88 Sidney St, Cambridge, MA 02139
Registration required

Speaker
Dr. Roger Kamm, Ph.D.
Depts. of Biological Engineering and Mechanical Engineering
Massachusetts Institute of Technology

 

 

Transport across the blood-brain barrier and subcutaneous delivery of ADCs: On the predictive power of in vitro models

Recent interest in the delivery of therapeutics to the brain has dramatically increased with the advent of new antigen drug conjugates (ADC) and other targeted delivery modalities for the treatment of dementias and glioblastoma.  In addition, subcutaneous delivery has been found to be an effective mode of ADC delivery, but the bioavailability in humans has been difficult to predict. These two factors have driven an increased interest in human cell-based in vitro models for screening novel delivery modalities and to gain mechanistic insight into the factors that control either entry into the brain or systemic bioavailability of subcutaneously delivered drugs.  In this presentation I will present models specifically developed for both applications and the potential for iPS cell-derived systems.  The benefits and current limitations of these models will also be addressed with the goal of stimulating an active discussion.

Sponsored by:

NEDMDG 2023 Winter Meeting
Wednesday December 6th, 2023 at 5:30 – 8:30 pm EST

Takeda Pharmaceuticals
35 Landsdowne St., Cambridge, MA
Registration required

Speaker
Dr. David Nettleton, Ph.D.
Associate Director
PK Sciences at Novartis Institutes for Biomedical Research

 

Abstract coming soon

Dave’s LinkedIn Profile

Sponsored by:

PAST EVENTS

NEDMDG 2023 Fall Meeting

Thursday September 14th, 2023 at 5:30 – 8:30 pm EST

Sanofi-Aventis
450 Water St., Cambridge, MA
Registration required

Dr. Yuichi Sugiyama, Ph.D.

Quantitative Prediction of the Hepatic Clearance and Complex Drug Interactions using PBPK Modeling with in vitro Transporter/enzyme Data

Studies have extensively investigated genetic polymorphisms (PGx) in drug transporters and the interplay of transporter/enzyme mediated drug-drug interactions (DDI). Such factors significantly influence the variability of drug responses among individuals. Early prediction of these differences during drug development is imperative. Through a PBPK model, it becomes feasible to predict the impacts of alterations in transporter/enzyme functions and abundance on pharmacokinetics (PK), pharmacodynamics (PD), and toxicodynamics (TD). Grasping the rate-determining process is essential for forecasting hepatic clearance, systemic exposure, and changes stemming from DDI and PGx. This insight facilitates the understanding of the “Extended clearance concept (ECC)” and the construction of a PBPK model. PBPK models serve as a cornerstone in translating in vitro data and evaluating DDI effects. Despite their use in drug regulatory submissions, their precision, especially regarding transporter-mediated DDIs and individual differences, continues to evolve.

Traditional IVIVE often doesn’t align perfectly with in vivo outcomes due to varied in vitro conditions and the challenge of emulating physiological systems. Consequently, the middle-out approach, which amalgamates a spectrum of in vitro measurements, is overshadowing the pure top-down method. This approach effectively employs the Claster Gauss-Newton Method (CGNM) algorithm (7,8). Using bosentan and warfarin as exemplars of small molecule drugs exhibiting target mediated drug disposition (TMDD), we developed a PBPK model incorporating saturation mechanisms for target binding and related PK processes. The PBPK model parameters were honed using CGNM, aligning with published data showcasing nonlinear PK profiles over extensive dose ranges. Our analysis indicates that for drugs like bosentan and warfarin, which interact with highly specific and high-affinity molecular targets, saturation in molecular target binding implies that in vivo molecular target occupancy profiles can be projected using solely dose-dependent drug concentration time profiles across a broad dose range.

Lastly, it’s pivotal to recognize that suboptimal IVIVE results are not setbacks but are avenues for discovery, spurred by scientific inquisitiveness. Such hurdles inspire the pursuit of innovative techniques, enriching our comprehension of the intricate nexus between in vitro and in vivo systems.

 References

  • Yoshikado T et al. Quantitative analyses of hepatic OATP-mediated interactions between statins and inhibitors using PBPK modeling with a parameter optimization method. Clin Pharmacol Ther. 100:513- (2016) 
  • Kim SJ et al. Extrapolation of In Vivo Hepatic Clearance from In Vitro Uptake Clearance by Suspended Human Hepatocytes for Anionic Drugs with High Binding to Human Albumin: Improvement of In Vitro-to-In Vivo Extrapolation by Considering the “Albumin-Mediated” Hepatic Uptake Mechanism on the Basis of the “Facilitated-Dissociation Model”. Drug Metab Dispos. 47:94-103 (2019).
  • Taskar KS et al. Physiologically-Based Pharmacokinetic Models for Evaluating Membrane Transporter Mediated Drug-Drug Interactions: Current Capabilities, Case Studies, Future Opportunities, and Recommendations.  Clin Pharmacol Ther. 107:1082-1115. (2020).
  • Asaumi R,et al. Expanded Physiologically-Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction. CPT Pharmacometrics Syst Pharmacol. 8:845-857 (2019).
  • Giacomini KM and Sugiyama Y. Membrane Transporters and Drug Response, in: Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 14e (Brunton LL and Knollmann BC eds), McGraw-Hill Education, New York, NY. (2023)
  • Fujino R et al. Strategies to improve the prediction accuracy of hepatic intrinsic clearance of three antidiabetic drugs: Application of the extended clearance concept and consideration of the effect of albumin on CYP2C metabolism and OATP1B-mediated hepatic uptake. Eur J Pharm Sci. 125:181-192 (2018)
  • Sugiyama Y and Aoki Y. A 20-Year Research Overview: Quantitative Prediction of Hepatic Clearance Using the IVIVE Approach Based on PBPK Modeling and Extended Clearance Concept Drug Metab Dispos. In press (2023)
  • Aoki Y et al. Cluster Gauss–Newton method. An algorithm for finding multiple approximate minimisers of nonlinear least squares problems with applications to parameter estimation of pharmacokinetic models. Optimization and Engineering  https://doi.org/10.1007/s11081-020-09571-2 (2020)
  • Koyama S et al. Revisiting nonlinear bosentan pharmacokinetics by PBPK modeling: Target binding, albeit not a major contributor to nonlinearity, can offer prediction of target occupancy. Drug Metab Dispos. 49:298-304 (2021)
  • Lee W, Min-Soo Kim MS, Aoki Y, Sugiyama Y(2023) ;  Predicting in vivo Target Occupancy (TO) P rofiles via PBPK-TO Modeling of Warfarin Pharmacokinetics in Blood: Importance of Low Dose Data and Prediction of Stereoselective Target Interactions Drug Metab Dispos.  In press (2023)
  • Burt T et al. Phase 0/microdosing approaches: time for mainstream application in drug development? Nature Reviews Drug Discovery 19: 801–818 (2020)

About Dr. Yuichi Sugiyama

Yuichi Sugiyama started working as the Special Professor Emeritus in Josai Interanational University as of April 1, 2021. Before that, Dr. Sugiyama has been the Head of Sugiyama Laboratory, RIKEN,Yokohama, Japan since April 2012. He has been Professor, Dept of Molecular Pharmacokinetics at the Univ of Tokyo since 1991 until 2012. Dr. Sugiyama is acknowledged as a world-leader in the fields of physiologically based pharmacokinetics and membrane transporters. His work on physiologically based pharmacokinetics has been pivotal for quantitative in vitro – in vivo extrapolation, especially the development of models for the prediction of drug clearance and the magnitude of drug-drug interactions in humans. Further, his studies on membrane transporters, which encompass functional and kinetic characterization, and the impact of genetic variation, have been fundamental to our understanding of the role of transporters in drug disposition. Dr. Sugiyama has been the recipient of many awards, including the AAPS Award in 2003, FIP Host-Madsen Medal in 2009, Medal with Purple Ribbon given by Government of Japan in 2010, BB Brodie Award from ASPET in 2012, Rawls-Palmer Progress in Medicine Award from ASCPT in 2014, the RT Williams Distinguished Scientific Achievement Award from ISSX in 2013 and The Order of the Sacred Treasure, Gold Rays with Neck Ribbon by Government of Japan 2020. In addition to his scientific work, Dr Sugiyama has held leadership positions in several scientific organizations. In particular, he has served as the Presidents of ISSX and JSSX and strongly promoted worldwide drug metabolism, disposition, transporter research.

NEDMDG 2023 In-person Spring Meeting

Wednesday March 29th, 2023 at 5:30 – 8:30 pm EST

Pfizer Inc.
610 Main St.
Cambridge, MA 02139
(Attendees should enter via the lobby that’s located on 1 Portland Street, Cambridge MA)

Registration required

SEMINAR

Nonclinical pharmacokinetics and biodistribution of VSV-GP using methods to decouple input drug disposition and viral replication

Joseph Ashour, Ph.D

Abstract: Viral replication places oncolytic viruses (OVs) in a unique niche in the field of drug pharmacokinetics (PK) as their self-amplification obscures exposure-response relationships. Moreover, standard bioanalytical techniques are unable to distinguish the input from replicated drug products. Here, we combine two novel approaches to characterize PK and biodistribution (BD) after systemic administration of vesicular stomatitis virus pseudotyped with lymphocytic choriomeningitis virus glycoprotein (VSV-GP) in healthy mice. First: to decouple input drug PK/BD versus replication PK/BD, we developed and fully characterized a replication-incompetent tool virus that retained all other critical attributes of the drug. We used this approach to quantify replication in blood and tissues and to determine its impact on PK and BD. Second: to discriminate the genomic and antigenomic viral RNA strands contributing to replication dynamics in tissues, we developed an in situ hybridization method using strand-specific probes and assessed their spatiotemporal distribution in tissues. This latter approach demonstrated that distribution, transcription, and replication localized to tissue-resident macrophages, indicating their role in PK and BD. Ultimately, our study results in a refined PK/BD profile for a replicating OV, new proposed PK parameters, and deeper understanding of OV PK/BD using unique approaches that could be applied to other replicating vectors.

This meeting is sponsored by

Sponsor Presentation

TBD

 

NEDMDG In-person Winter Meeting

Monday December 5th, 2022 at 5:30 – 8:30 pm EST

Takeda Pharmaceuticals Company
35 Lansdowne street,
Cambridge, MA 02139

Registration required

SEMINAR

Targeting liver with nucleic acid therapeutics for the treatment of liver-originated systemic diseases

Xiaobo Zhong, Ph.D

Abstract: Coming soon

This meeting is sponsored by

Sponsor Presentation

TBD

<<Short presentation prior to the webinar>>

 

NEDMDG In-person Fall Meeting 

Wednesday September 7th, 2022 at 5:30 – 8:30 pm EST

Novartis
181 Mass Ave,
Cambridge, MA 02139

Registration required

SEMINAR SERIES

Light Speed Development Approaches, Which Facilitated EUA Filing with PaxlovidTM

FIRST TOPIC

Innovative First-in-Human Study and Dosing Regimen Selection for Accelerated Development of Nirmatrelvir

Ravi Shankar Singh, PhD

Coronavirus disease 2019 (COVID-19) is a continued leading cause of hospitalization and death. Safe, efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) Mpro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. An accelerated 5-part FIH study including single-ascending dose (SAD), Multiple-ascending dose (MAD), relative bioavailability, food effect, Japanese PK, metabolism and excretion and supratherapeutic exposure cohorts was conducted to assess safety and pharmacokinetics of nirmatrelvir. Two interleaving SAD cohorts were evaluated in a three-period crossover. MAD with nirmatrelvir/ritonavir twice daily (b.i.d.) dosing was evaluated over 10 days parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase II/III clinical trials were supported by integrating modeling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). In SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well-tolerated. Nirmatrelvir exposure and half-life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase II/III trials (300/100 mg b.i.d.), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro. The QSP model suggested that a 5-day regimen would significantly decrease viral load in SARS-CoV-2-infected patients which may prevent development of severe disease, hospitalization, and death. In conclusion, an innovative and seamless trial design expedited establishment of phase I safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase II/III dose selection and accelerated pivotal trials’ initiation. The presentation will include the details of the planning and conduct of the study, pharmacokinetics and dosing regimen selection of nirmatrelvir

SECOND TOPIC

Metabolism and Disposition of Nirmatrelvir in Humans Using Fluorine NMR Instead of 14Carbon

R. Scott Obach, PhD

Typically human ADME studies are executed using radiolabeled (e.g., 14C) material, the synthesis of which is a time-consuming activity.  We were able to assess the metabolism and excretion of unlabeled nirmatrelvir (PF-07321332) within the first-in-human study via a novel application of quantitative fluorine NMR spectroscopy in place of a standard radiolabel ADME study. Six healthy subjects received a single 300-mg oral dose of nirmatrelvir (in combination with ritonavir), and excreta were collected up to 10 days. Virtually all drug-related material was recovered within 5 days, and mass balance was achieved with approximately 84.9 ± 8.9% (range=70.7–95.5%) of the administered dose recovered in urine and feces. Urine, fecal homogenate, and plasma pools were also analyzed for metabolite profiles by HPLC followed by 19F NMR quantitation of fractions. Metabolites were characterized and identified by HRMS. This successful demonstration of quantitative 19F NMR spectroscopy to establish the mass-balance, excretion, and metabolic profile of nirmatrelvir offers an advantageous means to execute human ADME studies for fluorine-containing compounds early in drug development.  The presentation will include specifics of how this was accomplished, in comparison to standard 14C ADME studies

This meeting is sponsored by

Sponsor Presentation

Interactions of Potential Anti-COVID-19 Compounds with Multispecific ABC and OATP Drug Transporters.

by Noemi Szili

<<Short presentation prior to the webinar>>

 

NEDMDG In-person Summer Meeting

Wednesday June 22nd, 2022 at 5:30 – 9:00 pm EST

Novartis
181 Mass Ave,
Cambridge, MA 02139

View Recording until September (Password 3^*u6ICC)

TOPIC

“Discovery and Visualization of Uncharacterized Drug-Protein Adducts Using Mass Spectrometry”

By Dr. Alex Zelter,

Department of Biochemistry, University of Washington

 

Drugs are often metabolized to reactive intermediates that form protein adducts. Adducts can inhibit protein activity, elicit immune responses, and cause life-threatening adverse drug reactions. The masses of reactive metabolites are frequently unknown, rendering traditional mass spectrometry-based proteomics approaches incapable of adduct identification. Here, we present Magnum, an open-mass search algorithm optimized for adduct identification, and Limelight, a web-based data processing package for analysis and visualization of data from all existing algorithms. Limelight incorporates tools for sample comparisons and xenobiotic-adduct discovery. We validate our tools with three drug/protein combinations and apply our label-free workflow to identify novel xenobiotic-protein adducts in CYP3A4. Our new methods and software enable accurate identification of xenobiotic-protein adducts with no prior knowledge of adduct masses or protein targets. Magnum outperforms existing label-free tools in xenobiotic-protein adduct discovery, while Limelight fulfills a major need in the rapidly developing field of open-mass searching, which until now lacked comprehensive data visualization tools

TOPIC

“Circumventing the Blood-Testis Barrier: Transporter-Mediated Therapeutic Delivery”

By Dr. Nathan J. Cherrington,

Professor and 1885 Society Distinguished Scholar

Department of Pharmacology and Toxicology at the University of Arizona

This meeting is sponsored by

Sponsor Presentation

“999Elite Cryopreserved Human Hepatocytes

<<Short presentation prior to the webinar>>

 

NEDMDG Winter Meeting Webinar

Wednesday December 8th, 2021 at 4:00pm EST

Recording Available Now

TOPIC

“The Nonclinical Disposition and PK/PD Properties of GalNAc-conjugated siRNA Are Highly Predictable and Build Confidence in Translation to Man”

By Dr. Robin McDougall,

Director Quantitative Pharmacology

Repare Therapeutics 

Our NEDMDG Fall Meeting Webinar

Tuesday September 21st, 2021 at 4:00pm EST

Recording available now

TOPIC

“Drug Phosphorylation by Adenylate and Creatine Kinases”

By Dr. Namandjé N. Bumpus,

E.K. Marshall and Thomas H. Maren Professor and Director

Department of Pharmacology and Molecular Sciences

Johns Hopkins University School of Medicine

 

To view recording, use passcode: &.xJ3gK1

Our NEDMDG Summer Meeting Webinar

 

This meeting is sponsored by

TOPIC

“Oral Inhibitors of the SARS-CoV-2 Main Protease for the Treatment of COVID-19”

By Dr. Dafydd Owen, Director of Medicinal Chemistry at Pfizer

Sponsor Presentation

Various Models and Delivery Methods in Ophthalmology Research:

A comprehensive discussion of the various disease models in ophthalmology available and under development at Biomere. 

Various routes of administration and assessments will be presented.

<<Short presentation prior to the webinar>>

 

TOPIC

“Plasma protein-mediated uptake of drugs and its impact in clearance prediction”

 

By Dr. David Hallifax from The University of Manchester

This meeting is sponsored by

Sponsor Presentation

Hepatic 3D-Spheroids for Detection of Drug Metabolites via High Resolution Mass Spectrometry

<<Short presentation prior to the webinar>>

 

TOPIC

“How DMPK Embraces its Role in Supporting Gene Therapy”

Gene therapy technology holds an enormous promise for patients in treating a variety of diseases. The rising numbers of clinical trials undeniably speak to this ever-expanding field.  Since the approval of Luxturna and Zolgensma, recombinant adeno-associated virus (rAAV)-as delivery vehicle further confirms its utility and continues to be the leading platform for gene therapy. While the multi-disciplinary functions within each company become more knowledgeable about rAAV-based gene delivery, the roles and responsibilities for each function also becomes more defined. DMPK plays a substantial role in advancing therapeutic gene therapy modality from preclinical research to clinical development, in particular  characterization of drug product biodistribution, immunogenicity assessment, and multiple platform bioanalytical assays and biomarker analysis, as well as first in human dose projection. The overview of each role, strategic approach to existing challenges and potential mitigation plans will be discussed.

 

By Dr. Nancy Chen from Takeda

This meeting is sponsored by

 

Our NEDMDG Spring Meeting will be held as a webinar on Wednesday September 23, 2020 at 10:00 am. 

 

TOPIC

“Drug metabolism by human gut microbes.”

Oral medicinal drugs can exhibit incomplete absorption in the upper gastrointestinal tract or reach the gut after enterohepatic circulation. In these circumstances, drugs encounter enormous densities of commensal microbes. These microbes collectively encode 150-fold more genes than the human genome, including a rich repository of enzymes with the potential to metabolize drugs. However, the contribution of the microbiome to drug and drug metabolite exposure in the GI tract and in circulation is largely unexplored.

I will describe examples that suggest that gut microbial activity can be responsible for a significant portion of systemic exposure to a toxic drug metabolite, even if the drug exhibits high bioavailability, if the same metabolite is readily produced by hepatic extracts in vitro, and if drug metabolite levels are low in feces. I will also introduce our efforts to explore the spectrum of microbiome-encoded drug metabolizing activities and to identify microbial genes that predict the capacity of an individual’s gut microbiome to metabolize a drug.

By Dr. Andrew Goodman from Yale University School of Medicine

Andrew L. Goodman, PhD, is the C. N. H. Long Professor of Microbial Pathogenesis at Yale University School of Medicine and Director of the Yale Microbial Sciences Institute. Goodman received his undergraduate degree in Ecology and Evolutionary Biology from Princeton University, his PhD in Microbiology and Molecular Genetics from Harvard University, and completed postdoctoral training at Washington University. His lab uses microbial genetics, gnotobiotics, and mass spectrometry to understand how the gut microbiome contributes to drug metabolism. The Goodman lab works to identify and characterize microbiome-encoded drug metabolizing enzymes, and to define how these microbial activities contribute to drug and drug metabolite exposure in the gut and in circulation. The lab’s contributions have been recognized by the NIH Director New Innovator Award, the Pew Foundation Research Scholars Program, the Dupont Young Professors Award, the Burroughs Wellcome Investigator in Infectious Disease Award, the Howard Hughes Medical Institute Faculty Scholars Program, and the Presidential Early Career Award in Science and Engineering.

This meeting is sponsored by

Our NEDMDG Winter Meeting will be held on Thursday, December 5, 2019 at TAKEDA PHARMACEUTICALS COMPANY, 35 LANSDOWNE STREET, CAMBRIDGE, MA 02139.

TOPIC

“The Drug Metabolism Scientist’s Contribution to the Development of Gene Therapies: It’s not what you do, it’s the way that you do it.”

By Dr. Mark Milton from Novartis

Please check back in a couple of weeks for more information about this event.

This meeting is sponsored by

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